CN113717188A - Alkaloid compound and application thereof - Google Patents
Alkaloid compound and application thereof Download PDFInfo
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Abstract
The invention discloses a new alkaloid compound in Chinese narcissus bulb. In vitro cell activity research shows that the novel compound separated from the bulb of Chinese narcissus has better inhibitory activity on T cells, and the compound can be developed and prepared into immunosuppressive drugs.
Description
Technical Field
The invention relates to a new compound with immunosuppressive activity, belonging to a narcissus alkaloid compound.
Background
Chinese Narcissus (Narcissus tazetta var. chinensis) is a perennial herb of Narcissus (Narcissus) in Amaryllidaceae, and its bulb has the effects of clearing away heat and toxic material, and resolving hard mass and relieving swelling. Research shows that the bulb of Chinese narcissus mainly contains alkaloid, flavone, flavan and derivatives thereof, lignan and other components, wherein the lycoris alkaloid is a special secondary metabolite thereof, has rich structure types, and is divided into lycorine, tennis-ball hydramine, dorsalicin, narcissin, galanthamine and the like according to different ring types.
In order to improve the comprehensive utilization efficiency of the medicinal plant resources of the Chinese narcissus, the inventor carries out systematic research on alkaloid components of the bulb part of the Chinese narcissus so as to discover an extract or a compound with biological activity.
Disclosure of Invention
The inventor finally obtains alkaloid compounds with good biological activity by extracting and purifying alkaloids in bulb parts of the Chinese narcissus.
Specifically, the invention provides a compound as shown in formula I, a pharmaceutically acceptable salt or a deuterated compound thereof, wherein the structural formula of the compound is as follows:
wherein R is selected from H, C1-C5 alkyl, -C (O) -R1, glycosyl;
the R1 is selected from saturated or unsaturated alkyl of C5-C11 and C13-C23.
In the present invention, the C1-C5 alkyl group may be selected from methyl, ethyl, propyl, butyl, etc.; can be further selected from C1-C3 alkyl.
In the present invention, the glycosyl may be selected from glycosyl groups commonly found in natural extracts, such as xylosyl, mannosyl, glucosyl, galactosyl, arabinosyl, glucuronyl, galacturonyl, rhamnosyl, and the like.
When R is selected from glycosyl, the compound is a glucoside structure, and the glycosidic bond can be naturally present in plant species or can be prepared by conventional glycosylation reaction.
In the present invention, the structure of the group-C (O) -is a carbonyl group.
Wherein, when R1 is selected from C5-C11 saturated or unsaturated alkyl groups, the-C (O) -R1 groups may be derived from medium chain fatty acids, such as caproic acid, caprylic acid, capric acid, lauric acid.
When R1 is selected from C13-C23 saturated or unsaturated alkyl groups, the-C (O) -R1 groups may be derived from long chain fatty acids, such as palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid.
When R is selected from-C (O) -R1, the compound can be obtained by isolation and extraction from plants, and can also be prepared by conventional esterification reaction.
The immunosuppressant in the invention is a medicine with an inhibitory effect on the immune response of an organism, can inhibit the proliferation and functions of cells (macrophages such as T cells, B cells and the like) related to the immune response, and can reduce the immune response of antibodies.
T lymphocytes (T lymphocytes), abbreviated as T cells, are bone marrow-derived lymphoid stem cells that, after differentiation and maturation in the thymus, are distributed through lymph and blood circulation to immune organs and tissues throughout the body to exert an immune function.
The alkaloid compounds have immunosuppressive activity, and can be used for preparing immunosuppressive drugs. Therefore, the invention also provides a pharmaceutical composition, and the active ingredients of the pharmaceutical composition comprise the alkaloid compounds and pharmaceutically acceptable auxiliary materials.
The pharmaceutical composition contains various pharmaceutically common additives (such as an excipient and the like) so as to prepare a pharmaceutical preparation. The pharmaceutical composition can be formulated into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, gels, emulsions, creams, granules, hard capsules, suppositories, and injections (solutions and suspensions, generally injections), etc., according to the therapeutic purpose. Preferably, the pharmaceutical composition is in the form of injection for local injection (e.g., subcutaneous, perineural, intra-articular cavity, etc.); alternatively, the pharmaceutical composition is in the form of gel, lotion, cream, etc., and can be applied topically; or the dosage form of the pharmaceutical composition is tablets, pills, powder, granules, hard capsules and the like, and the immunosuppressive effect is achieved through oral administration.
For shaping the pharmaceutical composition in tablet form, any excipient known and widely used in the art may be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like; binders such as water, ethanol, propanol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch, lactose and the like; disintegration inhibitors such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil; adsorption promoters such as quaternary ammonium bases and sodium lauryl sulfate, etc.; humectants such as glycerin, starch, and the like; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like; and lubricants such as pure talc, stearates, boric acid powder, polyethylene glycol, and the like. If desired, the tablets can also be made as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layer film tablets and multilayer tablets using customary coating materials.
For shaping the pharmaceutical composition in the form of a pill, any of the excipients known and widely used in the art may be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin, talc and the like; adhesives such as gum arabic powder, xanthan gum powder, gelatin, ethanol, and the like; disintegrating agents, such as agar and kelp powder.
For shaping the pharmaceutical composition in the form of suppositories, any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, and the like.
For preparing pharmaceutical compositions in the form of injection solutions, the solutions and suspensions may be sterilized and, preferably, suitable amounts of sodium chloride, glucose or glycerol, etc., may be added to make injection solutions which are isotonic with blood. In the preparation of ampoules, any of the carriers commonly used in the art may be used, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and fatty acid esters of polyethylene sorbitan, and the like. In addition, conventional lytic agents, buffers, analgesics, and the like may be added.
The content of the alkaloid compound and the pharmaceutically acceptable salt thereof in the pharmaceutical composition provided by the invention is not particularly limited, and can be selected within a wide range, and generally can be 0.1-99.9% by mass, preferably 1-70% by mass, and more preferably 1-30% by mass.
In the present invention, the method of administration of the pharmaceutical composition is not particularly limited. The formulation of various dosage forms can be selected for administration according to the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally; the injection can be simply used for intramuscular, intradermal, subcutaneous or intraabdominal injection; the suppository is administered to the rectum.
In the present invention, the administration dose can be appropriately selected depending on the administration method, the age, sex and other conditions of the patient and the symptoms. Typical dosages administered may be: about 0.01 to 300mg of the pharmaceutically active ingredient per kg body weight per day. Generally, each unit dosage form for administration may contain 1 to 200mg of the pharmaceutically active ingredient. The above preferred conditions can be combined arbitrarily to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
Other immunosuppressive agents may also be included in the combinations of the invention, for example (1) glucocorticoids, such as cortisone and prednisone; (2) microbial metabolites such as cyclosporine, tacrolimus, and the like; (3) antimetabolites such as azathioprine and 6-mercaptopurine, and the like; (4) polyclonal and monoclonal anti-lymphocyte antibodies, such as anti-lymphocyte globulin and OKT 3; (5) alkylating agents, such as cyclophosphamide and the like. One or more of (a).
Unless otherwise indicated, the terms and abbreviations disclosed herein have their standard meanings.
In the present invention, the deuterated compound refers to a compound obtained by substituting one or more hydrogens in the molecule of the alkaloid compound of the present invention with deuterium as an isotope.
Deuterium is a naturally occurring hydrogen isotope. Replacement of hydrogen with deuterium makes it possible to improve the pharmacokinetic parameters of the drug while ensuring the therapeutic effect.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows the NMR spectrum of Compound 1: (1H NMR);
FIG. 2 is a nuclear magnetic resonance carbon spectrum of Compound 1: (13C NMR);
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of Compound 2: (1H NMR);
FIG. 4 is a nuclear magnetic resonance carbon spectrum of Compound 2: (13C NMR);
FIG. 5 is the major HMBC correlation of compounds 1 and 2;
FIG. 6 is a graph relating the major NOESY of compounds 1 and 2.
Detailed Description
Example 1
Cutting 40 kg of fresh narcissus bulb by a vegetable cutter repeatedly, extracting for 2 times by methanol at 60 ℃, concentrating the extracting solution to obtain extract, dispersing by water, adjusting pH to 10 by ammonia water, extracting by n-butanol with the same volume to obtain total alkaloids (105G), carrying out normal phase silica gel column chromatography, carrying out gradient elution by chloroform-methanol (1:0-0:1) (each gradient has 3 column volumes), and combining similar components by TLC analysis to obtain A-G7 parts in sequence.
The fraction B (14g) was further subjected to normal phase silica gel column chromatography, gradient eluted with petroleum ether-acetone (15:1-1:1) (3 column volumes per gradient), concentrated and spotted to give 6 fractions B-1 to B-6, etc.
B-5(3.3g) was further subjected to ODS reverse phase column chromatography, eluting with methanol-water (0:1-1:1) gradients (4 column volumes per gradient), and after concentration, the similar fractions were combined on a dot-plate basis to give 5 fractions B-5-1 to B-5-5, etc.
B-5-2(55mg) was eluted with 20% methanol in water (1% TFA) and semi-preparative HPLC (C18 column 10 × 250mm,10 μm) gave compound 2(16mg,1mL/min, Rt 8 min).
The G fraction (40G) was subjected to ODS reverse phase column chromatography, eluted with methanol-water (0:1-1:0) gradient (4 column volumes per gradient), concentrated and spotted to give 4 fractions such as G-1 to G-4.
Wherein G-1(1.0G) was subjected to amino silica gel column chromatography eluting with a gradient of chloroform/methanol 40:1-20:1 (2 column volumes per gradient) to give compound 1(10mg) (compound 1 was obtained in a 30:1 gradient).
The physicochemical properties and spectral data of the obtained compounds 1, 2 are as follows:
compound 1: white amorphous powder, easily soluble in methanol and chloroform;UV(MeOH)λmax(logε):206(4.17),241(3.26),291(3.35);1H and 13c NMR data are shown in Table 1; HRESIMS M/z 288.1236[ M + H ]]+(calcd for C16H18NO4,288.1230). Is named as: 3-O-demethyl-6 a-deoxynorortazettine with chemical name of (3S,4aS,6aR,13bS) -3,4,4a,5,6,6a-hexahydro-8H- [1,3]dioxolo[4',5':6,7]isochromeno[3,4-c]indol-3-ol
Compound 2: white amorphous powder, easily soluble in methanol and chloroform;UV(MeOH)λmax(logε):207(4.28),241(3.36),293(3.47);1H and 13c NMR data are shown in Table 1; HRESIMS M/z 302.1392[ M + H ]]+(calcd for C17H20NO4,302.1387). Is named aS 6 a-deoxynorortazettine with the chemical name of (3S,4aS,6aR,13bS) -3-methoxy-3,4,4a,5,6,6a-hexahydro-8H- [1,3]dioxolo[4',5':6,7]isochromeno[3,4-c]indole。
The structural formulas of the compounds 1 and 2 are as follows:
TABLE 1 combination of 1H of objects 1 and 2 13NMR (400MHz) and C NMR (100MHz) data (i)n CD3OD)
Structure confirmation of the novel compounds:
Example 2:
immunosuppressive activity and beneficial effects of the novel compounds:
the following was conducted to evaluate the effects of the two alkaloid compounds provided by the present invention in terms of immunosuppression in combination with cell assay.
1) T cell isolation and purification protocol
Peripheral blood of healthy blood donors is taken and PBMC is separated by Ficoll density gradient centrifugation. "unaltered" (intact) CD4+ T cells were obtained from PBMC by negative selection using immunomagnetic bead separation. For specific operation, refer to Miltenyi company Pan T Cell Isolation Kit II (Human) specification. Purified CD4+ T cells, as detected by flow cytometry, had a cell positivity of greater than 95% for subsequent testing.
2) T cell stimulation protocol
The anti-CD3/CD28 mAbs were used to stimulate T cells and the specific assay procedures were performed as per routine procedures.
3) Detection of immunosuppressive Activity
T cells were obtained from human Peripheral Blood Mononuclear Cells (PBMC) using immunomagnetic bead separation. Laying 96-well plate, 2X 105A hole. Stimulating T activated proliferation by anti-CD3/CD28 mAbs, after 96hr, incubating the alkaloid compounds (1 and 2, concentration of 0.2,1,5,25 μ M in sequence) for 72hr, detecting the sample by CFSE staining combined with flow cytometry, and comparing with negative control (DMSO) to determine the inhibition effect of the sample on activated T cell proliferation.
4) Test results
The test result shows that the alkaloid compound shows good immunosuppressive activity and IC of the immunosuppressive activity on T cell proliferation5026.3 and 21.5 mu M (table 2) respectively, and discloses that the alkaloid compound provided by the invention has good application prospects in preparation of immunosuppressive drugs.
TABLE 2
And (4) conclusion: the alkaloid compound provided by the invention is a new compound which is separated for the first time, is determined to be a polychlorinated narcissus type lycoris alkaloid compound by an optical rotation, ultraviolet, nuclear magnetic resonance and mass spectrometry determination method, and represents a specific structure. The result of an immunosuppressive activity detection test shows that the compound has obvious inhibitory activity on T cell proliferation, IC5026.3 and 21.5 mu M respectively, thereby showing that the compound has better immunosuppressive activity, disclosing that the compound has good application prospect in preparing immunosuppressive drugs, can be used as a lead compound of immunosuppressive drugs, and is beneficial to the treatment of autoimmune diseases and immune rejection.
Claims (10)
3. the compound, pharmaceutically acceptable salt or deuterated compound thereof according to claim 1 or 2, wherein: the C1-C5 alkyl is selected from methyl, ethyl, propyl and butyl.
4. The compound, pharmaceutically acceptable salt or deuterated compound thereof according to claim 1 or 2, wherein:
r1 is selected from C5-C11 saturated or unsaturated alkyl, -C (O) -R1 is selected from caproic acid, caprylic acid, capric acid, lauric acid;
r1 is selected from C13-C23 saturated or unsaturated alkyl, and-C (O) -R1 is derived from palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid.
5. The compound, pharmaceutically acceptable salt or deuterated compound thereof according to claim 1 or 2, wherein: r is selected from H or methyl.
6. Use of a compound of any one of claims 1-4, a pharmaceutically acceptable salt thereof, or a deuterated compound thereof in the preparation of an immunosuppressant.
7. Use of a compound of any one of claims 1-4, a pharmaceutically acceptable salt thereof, or a deuterated compound thereof in the preparation of a T cell inhibitor.
8. Use of a compound of any one of claims 1-4, a pharmaceutically acceptable salt or a deuterated compound thereof in the manufacture of a product for treating an autoimmune disease; further, the autoimmune disease is selected from rheumatoid arthritis, lupus erythematosus, dermatomycosis, mesangial glomerulonephritis, inflammatory bowel disease, autoimmune hemolytic anemia, immune rejection.
9. A pharmaceutical composition characterized by: comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
10. The pharmaceutical composition of claim 9, wherein: also comprises one or more of glucocorticoid immunosuppressant, microbial metabolite immunosuppressant, antimetabolite immunosuppressant, polyclonal and monoclonal lymphocyte antibody immunosuppressant, and alkylating agent immunosuppressant.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1557313A (en) * | 2004-01-18 | 2004-12-29 | 中南大学 | Leukemia and myeloma treating plant extract and natural chemical monomer |
CN101352437A (en) * | 2007-09-13 | 2009-01-28 | 汕头大学医学院 | Use of amaryllidaceae alkaloid as tumour anti-apoptosis factor Mc1-1 inhibitor |
CN105384746A (en) * | 2015-12-13 | 2016-03-09 | 哈尔滨凝昇科技有限公司 | Method for extraction of tazettine from plant hymenocallis littoralis bulb |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1557313A (en) * | 2004-01-18 | 2004-12-29 | 中南大学 | Leukemia and myeloma treating plant extract and natural chemical monomer |
CN101352437A (en) * | 2007-09-13 | 2009-01-28 | 汕头大学医学院 | Use of amaryllidaceae alkaloid as tumour anti-apoptosis factor Mc1-1 inhibitor |
CN105384746A (en) * | 2015-12-13 | 2016-03-09 | 哈尔滨凝昇科技有限公司 | Method for extraction of tazettine from plant hymenocallis littoralis bulb |
Non-Patent Citations (2)
Title |
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NAIR, JERALD J.等: "Cytotoxic tazettine alkaloids of the plant family Amaryllidaceae", 《SOUTH AFRICAN JOURNAL OF BOTANY》 * |
毕玉蓉等: "水仙鳞茎分泌物中抑制物质的分离与鉴定", 《兰州大学学报( 自然科学版)》 * |
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